Topographical features and patterns on a surface of a medical device and methods of making the same

ABSTRACT

The invention relates to medical devices that has a surface configured to promote the migration of cells onto the surface of the medical device. In particular, the surface of the medical device has a noncontiguous pattern of topographical features formed therein or thereon.

CROSS REFERENCE TO RELATED APPLICATIONS

The present application is a continuation-in-part of U.S. patentapplication Ser. No. 13/654,923, filed Oct. 18, 2012, which is herebyincorporated by reference in its entirety.

The present application is related to co-pending and commonly owned U.S.patent application Ser. No. 13/103,576, filed May 9, 2011, which ishereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

The invention relates to methods and apparatus for manufacturing medicaldevices, wherein the medical device has a surface treated to promote themigration of cells onto the surface of the medical device.

Various types of intravascular stents have been used in recent years. Anintravascular stent generally refers to a device used for the support ofliving tissue during the healing phase, including the support ofinternal structures. Intravascular stents, or stents, placedintraluminally, as by use of a catheter device, have been demonstratedto be highly efficacious in initially restoring patency to sites ofvascular occlusion. Intravascular stents, or stents, may be of theballoon-expandable type, such as those of U.S. Pat. Nos. 4,733,665;5,102,417; or 5,195,984, which are distributed by Johnson & JohnsonInterventional Systems, of Warren, N.J., as the Palmaz™ and thePalmaz-Schatz™ balloon-expandable stents or balloon expandable stents ofother manufacturers, as are known in the art. Other types ofintravascular stents are known as self-expanding stents, such as Nitinolcoil stents or self-expanding stents made of stainless steel wire formedinto a zigzag tubular configuration.

Intravascular stents are used, in general, as a mechanical means tosolve the most common problems of percutaneous balloon angioplasty, suchas elastic recoil and intimal dissection. One problem intraluminal stentplacement shares with other revascularization procedures, includingbypass surgery and balloon angioplasty, is restenosis of the artery. Animportant factor contributing to this possible reocclusion at the siteof stent placement is injury to, and loss of, the naturalnonthrombogenic lining of the arterial lumen, the endothelium. Loss ofthe endothelium, exposing the thrombogenic arterial wall matrixproteins, along with the generally thrombogenic nature of prostheticmaterials, initiates platelet deposition and activation of thecoagulation cascade. Depending on a multitude of factors, such asactivity of the fibrinolytic system, the use of anticoagulants, and thenature of the lesion substrate, the result of this process may rangefrom a small mural to an occlusive thrombus. Secondly, loss of theendothelium at the interventional site may be critical to thedevelopment and extent of eventual intimal hyperplasia at the site.Previous studies have demonstrated that the presence of an intactendothelial layer at an injured arterial site can significantly inhibitthe extent of smooth muscle cell-related intimal hyperplasia. Rapidre-endothelialization of the arterial wall, as well asendothelialization of the prosthetic surface, or inner surface of thestent, are therefore critical for the prevention of low-flow thrombosisand for continued patency. Unless endothelial cells from another sourceare somehow introduced and seeded at the site, coverage of an injuredarea of endothelium is achieved primarily, at least initially, bymigration of endothelial cells from adjacent arterial areas of intactendothelium.

Although an in vitro biological coating to a stent in the form of seededendothelial cells on metal stents has been previously proposed, thereare believed to be serious logistic problems related to live-cellseeding, which may prove to be insurmountable. Thus, it would beadvantageous to increase the rate at which endothelial cells fromadjacent arterial areas of intact endothelium migrate upon the innersurface of the stent exposed to the flow of blood through the artery. Atpresent, most intravascular stents are manufactured of stainless steeland such stents become embedded in the arterial wall by tissue growthweeks to months after placement. This favorable outcome occursconsistently with any stent design, provided it has a reasonably lowmetal surface and does not obstruct the fluid, or blood, flow throughthe artery. Furthermore, because of the fluid dynamics along the innerarterial walls caused by blood pumping through the arteries, along withthe blood/endothelium interface itself, it has been desired that thestents have a very smooth surface to facilitate migration of endothelialcells onto the surface of the stent. In fact, it has been reported thatsmoothness of the stent surface after expansion is crucial to thebiocompatibility of a stent, and thus, any surface topography other thansmooth is not desired. Christoph Hehriein, et. al., Influence of SurfaceTexture and Charge On the Biocompatibility of Endovascular Stents,Coronary Artery Disease, Vol. 6, pages 581-586 (1995). After the stenthas been coated with serum proteins, the endothelium grows over thefibrin-coated metal surface on the inner surface of the stent until acontinuous endothelial layer covers the stent surface, in days to weeks.Endothelium renders the thrombogenic metal surface protected fromthrombus deposition, which is likely to form with slow or turbulentflow. At present, all intravascular stents made of stainless steel, orother alloys or metals, are provided with an extremely smooth surfacefinish, such as is usually obtained by electropolishing the metallicstent surfaces. Although presently known intravascular stents, specificincluding the Palmaz™ and Palmaz-Schatz™ balloon-expandable stents havebeen demonstrated to be successful in the treatment of coronary disease,as an adjunct to balloon angioplasty, intravascular stents could be evenmore successful and efficacious, if the rate and/or speed of endothelialcell migration onto the inner surface of the stent could be increased.

However, known topographical features, e.g., grooves, impart thegreatest benefit when the features are placed parallel with blood flowacross a medical device. No benefit from the topographical features isrealized when the features are oriented perpendicular to the flow ofblood.

Still further, maintaining this optimal orientation of the features canbe problematic for continuous features, since the final shape andorientation can depend on many factors. When the medical device is astent, the final shape, and expansion size, can vary depending on thecondition, size, shape, and compliance of the blood vessel where thestent is implanted. Similar implantation site factors can affect theorientation of topographical features on other implanted medicaldevices.

The present invention attempts to solve this problem, and others.

SUMMARY OF THE INVENTION

In accordance with the embodiments disclosed herein, at least onenoncontiguous pattern of topographical features is disposed in or on asurface of the device. The noncontiguous pattern of topographicalfeatures allows for cell migration in more than one direction, thuspermitting endothelial cells to migrate in the direction of blood flow,regardless of the final positioning of the medical device.

In one embodiment, there is provided a method of manufacturing a medicaldevice by first forming a device having at least one surface; and thenforming at least one noncontiguous pattern of topographical features inor on the surface of the device. The device may be any implantablemedical device, such as a stent.

Any type of cell is encompassed by the present invention, which cell hasa cellular membrane.

In accordance with the embodiments disclosed herein, the capacity forcomplete cell coverage of conventional implantable materials, includingmetals and polymers, may be enhanced by imparting a noncontiguouspattern of chemically and/or physiochemically active geometricphysiologically functional features onto a blood contacting surface ofthe implantable material. The inventive implantable devices may befabricated of polymers, pre-existing conventional wrought metallicmaterials, such as stainless steel or nitinol hypotubes.

In any embodiment, an existing medical device, stent, or other articlemay be utilized. Through the use of an existing structure, it is likelythat the regulatory path may be minimized. Particular, non-limitingdevices include dental implants and hip implants.

The noncontiguous pattern of topographical features, when compared withpresently known devices and methods for manufacturing such devices,improves the control of various cell responses at the surface of themedical device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a block diagram illustrating a method of manufacturing amedical device having at least one noncontiguous pattern oftopographical features created in or on a surface thereof.

FIG. 2 is a block diagram illustrating a method of manufacturing anintravascular stent having at least one noncontiguous pattern oftopographical features created in or on the inner surface thereof.

FIG. 3 is a block diagram illustrating a method of manufacturing atransparent apparatus having a surface adapted to mount a medical devicethereupon, so as to impart a photomask pattern to a surface of themedical device.

FIG. 4 is a block diagram illustrating a method of manufacturing atransparent mandrel for mounting an intravascular stent thereon, so asto impart a photomask pattern to the inner surface of the stent.

FIG. 5a is an illustration of one embodiment of a stent having anoncontiguous pattern of topographical features imparted in an innersurface of the stent; FIG. 5b is a close up view of a portion of FIG. 5a.

FIGS. 6a-6b is an illustration of a stent having a pattern of continuousgrooves in an inner surface of the stent.

FIGS. 7a-7c are illustrations of different noncontiguous patterns oftopographical features imparted in a surface of a medical device.

FIGS. 8a-8f are illustrations of different noncontiguous patterns oftopographical features imparted in a surface of a medical device.

FIG. 9 is an illustration of one embodiment of the transparent mandrelof the present invention, having a photoresist coated stent mountedthereupon.

FIG. 10a is an illustration of one embodiment of an implantable medicaldevice having surfaces imparted with topographical features; FIG. 10b isan illustration of one embodiment of an implantable medical devicehaving surfaces imparted with topographical features, wherein thefeatures include directional grooves and dots/pins.

FIG. 11a is an illustration of a dental implant having topographicalfeatures; FIG. 11b is an enlarged view of a portion of the dentalimplant of FIG. 11 a.

FIG. 12a is an illustration of a hip implant having topographicalfeatures; FIG. 12b is an enlarged view of a portion of the hip implantof FIG. 12a ; and FIG. 12c is an enlarged view of a distal portion ofthe hip implant of FIG. 12 a.

FIG. 13a is an illustration of a heart valve with grooves andnoncontiguous dots; and FIG. 13b is an enlarged view of a portion of theheart valve of FIG. 13 a.

While the invention will be described in connection with the preferredembodiment, it will be understood that it is not intended to limit theinvention of that embodiment. On the contrary, it is intended to coverall alternatives, modifications, and equivalents, as may be includedwithin the spirit and scope of the invention as defined by the appendedclaims.

DETAILED DESCRIPTION OF THE INVENTION

In one embodiment, the formation of the noncontiguous pattern oftopographical features may be by etching the surface with a chemicalprocess. Preferably, the chemical process may comprise the steps ofcoating the surface of the device with a photosensitive material;mounting the device on a mask; irradiating the surface of the device bya source of exposing radiation; removing the device from the mask; andetching light exposed areas to produce at least one noncontiguouspattern of topographical features in or on the surface of the device.The mask may be disposed upon a surface of a transparent apparatusadapted to have the device mounted thereupon, and the device is mountedon the transparent apparatus. The source of exposing radiation may be anultraviolet light source, but could be a light source with anywavelength compatible with the photosensitive material. Alternatively,the exposing radiation may be atomic in nature. The exposing radiationmay be transmitted through one edge of the apparatus, or transmitted bymeans of a fiber optic cable inserted within the apparatus below themask. If a fiber optic cable is used, either an end transmitting fiberoptic cable may be translated within the apparatus to gain evenexposures, or a bare (preferably frosted) fiber may be used to broadcastthe exposing radiation from within the apparatus. After exposure, thedevice is removed from the apparatus. The photosensitive material isdeveloped to reveal the pattern imparted by the mask by exposing thebase material of the device through the use of appropriate chemicals.The exposed base material of the device may then be chemically machinedto a desired depth. The machining may be accomplished by wet or drychemical etching or polishing, or by electrochemical machining.

The process will be able to follow the contours of the device bypatterning. For example, the mask pattern can be created such that thegroove pattern is altered to allow for the expansion of the stent suchthat the grooves are parallel to bloodflow after expansion by accountingfor the deformation pattern of the stent. Alternatively, patterns can betailored to steer cells in a particular direction. Any 2D or 3D patterncan be effectively embossed or debossed (or combination of both) in thesurface. Alternatively, other methods may be used to create the mask,including, but not limited to electrical discharge machining, dryetching, photodegradation, waterjet, abrasive blasting to create themask pattern. Additive methods are feasible as well where the maskingmaterial is added to the translucent member. An example of an additivemethod is inkjet technology to deposit a coating selectively to create apattern that would block the light transmission. Any material that canblock the exposure wavelength can be used as the mask, including metals,pseudometals, intermetallics, ceramics, polymers, and the like.

Although photolithography methodologies are discussed herein as a methodof forming the noncontiguous pattern of topographical features, thepresent invention is not so limited. Any methodology to form thenoncontiguous pattern of topographical features may be utilized,including photolithography, mechanical transfer, electrochemicalmachining, laser etching, electric discharge machining, and/or any othermeans of applying the pattern to a surface of the medical device.Generally, the present invention may comprise forming or providing amedical device having at least one surface and forming at least onenoncontiguous pattern of topographical features in or on said surface.

Any type of cell is encompassed by the present invention, which cell hasa cellular membrane. Most distinct cell types arise from a singletotipotent cell that differentiates into hundreds of different celltypes during the course of development. Multicellular organisms arecomposed of cells that fall into two fundamental types: germ cells andsomatic cells. During development, somatic cells will become morespecialized and form the three primary germ layers: ectoderm, mesoderm,and endoderm. After formation of the three germ layers, cells willcontinue to specialize until they reach a terminally differentiatedstate that is much more resistant to changes in cell type than itsprogenitors. The ectoderm differentiates to form the nervous system(spine, peripheral nerves and brain), tooth enamel and the epidermis(the outer part of integument). It also forms the lining of mouth, anus,nostrils, sweat glands, hair and nails. The endoderm forms thegastrointestinal tract cells, the respiratory tract cells, the endocrineglands and organ cells, the auditory system cells, and the urinarysystem cells. The mesoderm forms mesenchyme (connective tissue),mesothelium, non-epithelial blood cells and coelomocytes. Mesotheliumlines coeloms; forms the muscles, septa (cross-wise partitions) andmesenteries (length-wise partitions); and forms part of the gonads (therest being the gametes).

In accordance with the embodiments disclosed herein, the capacity forcomplete cell coverage of conventional implantable materials, includingmetals and polymers, may be enhanced by imparting a noncontiguouspattern of chemically and/or physiochemically active geometricphysiologically functional features onto a blood contacting surface ofthe implantable material. The inventive implantable devices may befabricated of polymers, pre-existing conventional wrought metallicmaterials, such as stainless steel or nitinol hypotubes.

The inventive implantable devices may be intravascular stents,stent-grafts, grafts, heart valves, venous valves, filters, occlusiondevices, catheters, sheaths, osteal implants, implantablecontraceptives, implantable antitumor pellets or rods, shunts andpatches, pacemakers, needles, temporary fixation rods, medical wires ormedical tubes for any type of medical device, or other implantablemedical devices, as will also be hereinafter described. A pacemaker (orartificial pacemaker, so as not to be confused with the heart's naturalpacemaker) is a medical device that uses electrical impulses, deliveredby electrodes contacting the heart muscles, to regulate the beating ofthe heart. The electrodes may be covered by tubing or other materialthat includes a surface that may require endothelialization and groovesthereon. Earrings and other piercings may benefit from the topographicalfeatures, as well as any other implant, whether the implant is anorganic, inorganic, mechanical, electrical, or biological device.

Although photolithography methodologies are discussed herein as a methodof forming the noncontiguous pattern of topographical features, thepresent invention is not so limited. Any methodology to form thenoncontiguous pattern of topographical features may be utilized,including photolithography, mechanical transfer, electrochemicalmachining, laser etching, electric discharge machining, and/or any othermeans of applying the pattern to a surface of the medical device.Generally, the present invention may comprise forming or providing amedical device having at least one surface and forming at least onenoncontiguous pattern of topographical features in or on said surface.

Adding topographical or groove features to the surface of a stent hasbeen shown to accelerate the migration rate of cells. However,topographical or groove features impart the greatest benefit when thetopographical or groove features are placed parallel with fluid flow,and provide little to no benefit when the topographical or groovefeatures are oriented perpendicular to the fluid flow. Thisperpendicular orientation can be problematic for continuoustopographical or groove features, since the final shape or orientationof the features can vary depending on the condition, size, shape, and/orcompliance of the blood vessel, lumen, or tissue where the device isimplanted.

The device design itself may also not be well suited for continuoustopographical or groove features. Some geometries do not allow for cellmigration across all areas of the device, without the cells travelingover the vessel or lumen wall. One such example of a continuous groovefeature can be seen in FIG. 6a . If evenly spaced, some topographical orgroove features may only allow for a very small distance of travel, asseen in region 600 of FIG. 6a . Still further, a stent with a largeexpansion ratio can result in more grooves losing their properorientation with blood flow. FIG. 6b illustrates a similar stentgeometry to FIG. 6a , however a noncontiguous pattern of topographicalfeatures 650 is imparted to a surface of the stent. As can be seen,regardless of the orientation of the stent, cells may migrate across allareas of the stent, unlike with the continuous grooves in FIG. 6 a.

A noncontiguous topographical pattern 520 on at least one surface 510 ofa medical device 500 allows for cell migration in more than onedirection, as shown in FIGS. 5a-b . The noncontiguous pattern allows thecells to migrate in the direction of blood flow, regardless of the finalpositioning of the surfaces or structures of the medical device. In oneembodiment, the noncontiguous topographical pattern 520 includes aplurality of grooves 530 forming a triangular shape 540 on the surface510 of the device 500. The triangular shapes 540 alternate in facing onedirection and then the opposite direction, as to form a row ofalternating facing triangular shapes 540.

The pattern itself could be any noncontiguous shape that promotes afavorable cell response, as further discussed below in relation to FIGS.7a-7b . The shapes could be of any size, number, height, or depthrequired to issue a proper cell response. The limit of the distance forthe noncontiguous pattern may be across a particular length or depth. Inone embodiment, the noncontiguous pattern includes a continuous groovefor at least 0.1-5.0 microns in length, alternatively, at least 10.0microns in length, alternatively, at least 1.0-100.0 microns in length.Then noncontiguous groove is placed at an angle thereafter, preferablybetween about 10-150 degrees, alternatively, between about 20-120degrees, alternatively, between about 30-100 degrees. In one embodiment,the noncontiguous pattern may take place after 5-10 microns of groovelength. In one embodiment, the noncontiguous pattern may be sinusoidalpattern 720 of curved lines, as shown in FIG. 7C. The sinusoidal pattern720 of curved lines may have a specific wavelength and amplitude, mayhave a constant amplitude and wavelength, or may a discontinuousamplitude and wavelength that varies along the length of the groove. Thewavelength and the amplitude of the sinusoidal pattern 720 may be atleast 0.1-5.0 microns in length, alternatively, at least 10.0 microns inlength, alternatively, at least 1.0-100.0 microns in length

Alternatively, as shown in FIG. 8A, the noncontiguous shapes may includeintermatched shaped pattern 800, such as alternating octagonal groovedfeatures 802 displaced with square grooved features 804. Alternatively,the noncontiguous pattern may be alternating diagonal groove patternwith alternating diagonal groove 812 and 814 displaced at an angle, asshown in FIG. 8B. Alternatively, the noncontiguous pattern may beboomerang like shape 820 with three prongs 822 stemming from curvedportions 824, wherein the end of each prong 820 abuts an adjacent curvedportion 824, as shown in FIG. 8C. Alternatively, the noncontiguouspattern may be zig-zag like grooved feature 830, where the every fourthzig-zag groove 832 includes a depth greater than the previous groovedfeatures 834, as shown in FIG. 8D. Alternatively, the noncontiguouspattern may include general hexagonal pattern 840 with at least threealternating diagonal groove features 842 disposed within each hexagonalpattern 830 and the plurality of diagonal groove features 842 terminateat an angle into a length of an adjacent diagonal groove feature 842, asshown in FIG. 8E. Alternatively, the noncontiguous pattern may includeopen hexagonal grooved features 850 whereby an inner hexagonal groove852 encircles an outer hexagonal groove 854 about at least one point,and the inner hexagonal groove 852 may be a different width or depththan the outer hexagonal groove 854, as shown in FIG. 8F.

These features could be added to surfaces of articles other than stents.The term “stent” is used throughout this application to simplify theexplanation, but is not intended to be a limiting description. As statedabove, the inventive implantable devices may be intravascular stents,stent-grafts, grafts, heart valves, venous valves, filters, occlusiondevices, catheters, sheaths, osteal implants, implantablecontraceptives, implantable antitumor pellets or rods, shunts andpatches, pacemakers, needles, temporary fixation rods, medical wires ormedical tubes for any type of medical device, or other implantablemedical devices, as will also be hereinafter described.

Using photolithography, mechanical machining, micromachining, lasermachining, or other means to transfer the pattern, a pattern of multiplenon-contiguous shapes can be produced in or on the surface of animplantable medical device to promote healing, by allowing for cellmigration in the direction of blood flow regardless of alignment of thedevice after implantation. The noncontiguous pattern of topographicalfeatures may be created through photolithography, mechanical transfer,electrochemical machining, or any other means of applying the pattern toa surface of the device. These new techniques embodied in the presentinvention described herein provide the opportunity to apply not justgrooved features, but any conceivable pattern of shapes.

Additionally, not only may these patterns be utilized for cellmigration, but also to allow for cells to spread quickly to the sidesonce the path in the direction of blood flow is occupied by existingcells. This may be particularly useful for specific implantable medicaldevices, such as heart valves.

In still further embodiments, the noncontiguous pattern of topographicalfeatures can be used to promote other cell responses, such as demotingcell proliferation, pinning cells in place, thwarting tissue growth,enhancing osteoblast formation, and/or the like. Surface modificationcould include geometric features, charge distribution, alternativechemistry for the patterns, coatings on the patterns, oxides on thepatterns, nitrides on the patterns, and the like.

Pattern Shape

The pattern itself could be any noncontiguous shape that promotes afavorable cell response. The shapes could be of any size, number,height, or depth required to issue a proper cell response. Illustrationsof exemplary patterns are shown in FIGS. 7-8. FIG. 7A depicts ahexagonal noncontiguous pattern of topographical features 700. FIG. 7Bdepicts a triangular noncontiguous pattern of topographical features800. FIG. 8 depicts an intermatched shaped pattern 800, such asalternating octagonal grooved features 802 displaced with square groovedfeatures 8040.

Additionally, in further embodiments, the noncontiguous pattern oftopographical features could be placed anywhere on a surface of thedevice, could be used on external surfaces of the device to prevent cellmigration, or could be used for drug delivery. For example, consideringa disposable device such as a needle used with an insulin pump, it maybe advantageous to thwart tissue growth to ease removal of the temporarydevice. Other similar devices may include temporary fixation rods usedfor knee, shoulder, or elbow repair, and/or the like. Devices with anoncontiguous pattern of topographical features may also be useful forpromoting healing at closure sites, or for bone mending (such as thebreastplate after open heart surgery).

In some embodiments, multiple noncontiguous patterns of topographicalfeatures may be imparted to a single device, such as on differentsurfaces or different portions of a surface, to achieve different cellresponses for different objectives. For example, considering a heartvalve, a first noncontiguous pattern of topographical features could beincorporated in the anchoring portion of the heart valve and a secondnoncontiguous pattern of topographical features incorporated near theleaflets of the valve to prevent tissue growth on the leaflets.

With reference to FIG. 1, the method of creating a noncontiguous patternof topographical features on a surface of a medical device 100 isillustrated. First, a medical device is provided 105. In a preferredembodiment, the medical device is metallic in nature, but need only besuitable for chemical machining. Photoresist is then applied to thedevice and treated appropriately to make the photoresist photosensitive110. A positive or negative photoresist may be used. In a preferredembodiment, the photoresist is an electrodeposited positive photoresist(InterVi™ 3D-P Photoresist PEPR-2400) from MicroChem. Alternativephotoresists are contemplated by and within the scope of thisdisclosure, including negative photoresist. By electrodepositing thephotoresist, all surfaces of the device are easily coated with a uniformlayer of resist, as compared to traditional photoresist applicationmethods. It is important to attain sufficient control over coatingthickness on especially the inner diameter of the stent. In alternativeembodiments, the device may be coated with photoresist by dipping,spraying, spinning, electrodeposition, or any other typical means ofapplying photoresist. Once the device is coated, the device is mountedon a photomasked transparent apparatus 115. The method of creating thephotomasked transparent apparatus is discussed further below, inrelation to FIG. 3. In mounting the device on the photomasked apparatus,it is preferable to maintain intimate contact between the device andapparatus, to aid in pattern transfer. In one embodiment, an externalforce is applied to the device to obtain this intimate contact. Inanother embodiment, an interference fit between the apparatus and thedevice can be used to obtain the intimate contact. In embodiments wherethe device is nitinol-based, the interference fit may be obtained byshape memory. Once the device is mounted on the apparatus, thephotoresist coating on the device is exposed to exposing radiationthrough the photomasked apparatus 120. In a preferred embodiment, theexposing radiation is an ultraviolet light source, though the lightsource could have any wavelength that is compatible with the particularphotoresist utilized by the inventive method. One such source is a lightguide or an internal 0.7 mm fiber with UV radiation provided by a 200 WLesco SuperSpot Max-HP source. In an alternative embodiment, theexposing radiation may be atomic in nature. The exposing radiation maybe transmitted through one edge of the apparatus, or transmitted bymeans of a fiber optic cable inserted within the apparatus below thephotomask. If a fiber optic cable is used, either an end transmittingfiber optic cable may be translated within the apparatus to gain evenexposures, or a bare (preferably frosted) fiber may be used to broadcastthe exposing radiation from within the apparatus. After exposure, thenow exposed device is removed from the apparatus 125. The exposedphotoresist is then developed to reveal the noncontiguous patternimparted by the photomask 130. In one embodiment, a rinse process maythen be employed on the exposed photoresist to enhance pattern coverageand give rise to about 100% pattern coverage. Some metals may a rinse ofwarmed deionized water, while other metals may not require the rinsestep. In the preferred embodiment, using a positive photoresist,developing exposes the base material of the device in the exposedportions of the photoresist through the use of appropriate chemicals. Inthe preferred embodiment, the appropriate chemicals are thoserecommended by the manufacturer of the photoresist, including InterVia™3D-P Developer, InterVia™ 3D-P Remover, InterVia™ 3D-P Solvent, andInterVia™ 3D-P TC. The exposed base material of the device may then bechemically machined to a desired depth 1350. The machining may beaccomplished by wet or dry chemical etching or polishing, or byelectrochemical machining. In one embodiment, the electrochemicalmethods are carried out in a phosphoric acid bath. Once the machining iscomplete, the remaining photoresist may be removed from the device 140,by appropriate means. Appropriate means may include chemical ormechanical removal of the remaining photoresist. The result is a medicaldevice having a noncontiguous pattern of topographical features createdon at least one surface of the device.

In a further embodiment, after the machining is complete, the patterningand machining process can be repeated using additional transparentapparatuses, having distinct photomask patterns, to achievemultiple-depth noncontiguous patterns of topographical features on thesurface of the device. Alternatively, the patterning and machiningprocess can be repeated to impart distinct noncontiguous patterns oftopographical features to different portions or surfaces of the device,having the same or different depths, patterns, shapes, etc.

With reference to FIG. 2, the method of creating a noncontiguous patternof topographical features on the inner diameter surface of anintravascular stent 200 is illustrated. First, an intravascular stent isprovided 205. In a preferred embodiment, the intravascular stent ismetallic in nature, but the material of the intravascular stent needonly be suitable for chemical machining. Photoresist is then applied tothe stent and treated appropriately to make the photoresistphotosensitive 210. In a preferred embodiment, the photoresist is anelectrodeposited positive photoresist (InterVia™ 3D-P PhotoresistPEPR-2400) from MicroChem. Alternative photoresists are contemplated byand within the scope of this disclosure, including negative photoresist.If a negative photoresist is used, additional steps are required toexpose the masked portions of the stent and then expose the remainingsurfaces. By electrodepositing the photoresist, all surfaces of thestent are easily coated with a uniform layer of resist, as compared totraditional photoresist application methods. It is important to attainsufficient control over coating thickness on especially the innerdiameter of the stent. In alternative embodiments, the stent may becoated with photoresist by dipping, spraying, spinning,electrodeposition, or any other typical means of applying photoresist.Once the stent is coated, the stent is mounted on a photomaskedtransparent mandrel 215. The method of creating the photomaskedtransparent mandrel is discussed further below, in relation to FIG. 4.In mounting the stent on the photomasked mandrel, it is preferable tomaintain intimate contact between the stent and the mandrel, to aid inpattern transfer. In one embodiment, an external force is applied to thestent to obtain this intimate contact. In another embodiment, aninterference fit between the mandrel and the stent can be used to obtainthe intimate contact. In embodiments where the stent is nitinol-based,the interference fit may be obtained by shape memory. Once the stent ismounted on the mandrel, the photoresist coating on the stent is exposedto exposing radiation through the photomasked mandrel 220. In apreferred embodiment, the exposing radiation is an ultraviolet lightsource, though the light source could have any wavelength that iscompatible with the particular photoresist utilized by the inventivemethod. One such source is a light guide or an internal 0.7 mm fiberwith UV radiation provided by a 200 W Lesco SuperSpot Max-HP source. Inan alternative embodiment, the exposing radiation may be atomic innature. The exposing radiation may be transmitted through one end of themandrel, or transmitted by means of a fiber optic cable inserted withinthe mandrel below the photomask. If a fiber optic cable is used, eitheran end transmitting fiber optic cable may be translated within themandrel to gain even exposures, or a bare (preferably frosted) fiber maybe used to broadcast the exposing radiation from within the mandrel. Inone embodiment, certain light guide with high optical numerical aperture(NA) produces the pattern definition of the noncontiguous pattern. Lightguides and fibers preferably emit optical radiation radially. Thetranslated fibers may include a conical tip as the optical radiationexits at a perpendicular angle to the mask. The methods of illuminatingthe mask may include: 1) end lighting, which relies on internalreflection and transmission through the mask; 2) a diffuse internallight that broadcasts over an area large enough to expose the entirearticle (or multiple articles) without having to move the light relativeto the mask; and 3) an end lit internal fiber that is translated insidethe mask to expose the article one section at a time in a continuousmanner. The third method allows for very long lengths to be exposed. Inaddition, the exposure can be varied or interrupted, if desired. Thesecond method can also work using translation to expose longer lengtharticles.

After exposure, the now exposed stent is removed from the mandrel 225.The exposed photoresist is then developed to reveal the noncontiguouspattern imparted by the photomask 230. In the preferred embodiment,using a positive photoresist, developing exposes the base material ofthe stent in the exposed portions of the photoresist through the use ofappropriate chemicals. In the preferred embodiment, the appropriatechemicals are those recommended by the manufacturer of the photoresist,including InterVia™ 3D-P Developer, InterVia™ 3D-P Remover, InterVia™3D-P Solvent, and InterVia™ 3D-P TC. The exposed base material of thestent may then be chemically machined to a desired depth 235. Themachining may be accomplished by wet or dry chemical etching orpolishing, or by electrochemical machining. In one embodiment, theelectrochemical methods are carried out in a phosphoric acid bath. Oncethe machining is complete, the remaining photoresist may be removed fromthe stent 240, by appropriate means. Appropriate means may includechemical or mechanical removal of the remaining photoresist. The resultis an intravascular stent having a noncontiguous pattern oftopographical features created on an inner diameter surface of thestent.

With reference to FIG. 3, the method of manufacturing a photomaskedtransparent apparatus 3000 is illustrated. First, a transparentapparatus is provided 305. In a preferred embodiment, the transparentapparatus is comprised of quartz, glass, or any other material capableof transmitting an exposing radiation through a photomask onto aphotoresist coated medical device. The transparent apparatus has atleast one surface adapted to mount a medical device thereupon. The atleast one surface of the transparent apparatus is then coated with anopaque layer 310. In one embodiment, the opaque layer is a thin wallmaterial on the top or bottom of the at least one surface. In anotherembodiment, the opaque layer may be a metal, a polymer, a composite, aceramic, or any other material that sufficiently blocks the transmissionof the exposing radiation. The opaque layer may be deposited by severalmethods, including: dipping, spraying, vapor deposition, plating, orpainting. Once coated, portions of the opaque layer may be selectivelyremoved from the transparent apparatus by appropriate means 315, so asto form a photomask pattern on the surface of the apparatus. Theappropriate means may include laser ablation, mechanical means,photolithography, etching, or engraving, and/or the like. With portionsof the opaque layer removed, an exposing radiation is able to betransmitted through the now photomasked surface of the transparentapparatus.

With reference to FIG. 4, the method of manufacturing a photomaskedtransparent apparatus 400 is illustrated. First, a transparent mandrelis provided 405. In a preferred embodiment, the transparent mandrel iscomprised of quartz, glass, or any other material capable oftransmitting an exposing radiation through a photomask onto aphotoresist coated intravascular stent. In one embodiment, the mandrelis a cylindrical tube or rod. In alternative embodiments, the mandrelmay be tapered, have an elliptical cross section, or have a polygonalcross section. The transparent mandrel has at least one surface adaptedto mount an intravascular stent thereupon. In one embodiment, themandrel has at least one open end, within which a fiber optic cable maybe inserted for transmittal of the exposing radiation from within themandrel through a photomask on the exterior of the mandrel. The at leastone surface of the transparent mandrel is then coated with an opaquelayer 410. In one embodiment, the opaque layer is a thin wall tubedisposed against the inner or outer surface of the cylindrical mandrel.In another embodiment, the opaque layer may be a metal, a polymer, acomposite, a ceramic, or any other material that sufficiently blocks thetransmission of the exposing radiation. The opaque layer may bedeposited by several methods, including: dipping, spraying, vapordeposition, plating, or painting. In the preferred embodiment, ametallic coating is deposited by physical vapor deposition on the outersurface of a cylindrical quart tube. Once coated, portions of the opaquelayer may be selectively removed from the transparent mandrel byappropriate means 415, so as to form a photomask pattern on the surfaceof the mandrel. The appropriate means may include laser ablation,mechanical means, photolithography, etching, or engraving, and/or thelike. In the preferred embodiment, the opaque layer is removed by laserablation, utilizing a femtosecond laser cutting system. With portions ofthe opaque layer removed, an exposing radiation is able to betransmitted through the now photomasked surface of the transparentmandrel. Another method of producing the transparent mandrel is throughthe use of photolithography and chemical etch processes, which includesa photosensitive polymer coated on the mandrel and UV is appliedselectively (e-beam or UV projection method).

With reference to FIG. 9, one embodiment of the photomasked transparentmandrel having a photoresist coated stent is depicted. The transparentmandrel 900 is has a photoresist coated intravascular stent 905 mountedon the outer surface of the mandrel. The outer surface of the mandrel iscoated with an opaque layer 910. Portions of the opaque layer 910 havebeen selectively removed to form a mask pattern, the mask patterncomprising openings 915 where the opaque layer has been removed.

In another embodiment of the present invention, the machined pattern maybe used to enhance bone formation by enhancing osteoblast production fordevices such as, but without limitation to, orthopedic or dentaldevices.

Referring to FIG. 10A, a structural member 1006 includes a luminalsurface 1036 as well as a leading edge 1014 and a trailing edge 1016relative to the direction 1010 of blood flow. Any or all of the luminalsurface 1036, the leading edge 1014, and the trailing edge 1016 mayinclude topographical features disposed therein or thereon. For example,in one embodiment, the topographical features of luminal surface 1036may be grooves 1018 disposed therein, and is noncontiguous by virtue ofthe edge of the structural member. The grooves 1018 may be oriented inany direction relative to the direction 1010 of blood flow; however,orientation of the grooves 1018 parallel to the direction 1010 of bloodflow, as illustrated in FIG. 10A, exposes EC within the grooves 1018 toshear stress caused by the blood flow. As noted hereinabove, suchexposure of EC to shear stress increases the rate of migration of theEC.

The leading edge 1014 of the structural member 1006, in one embodiment,may have topographical features such grooves 1020 disposed therein orthereon. The grooves 1020 may be oriented in any direction relative tothe direction 1010 of blood flow and is noncontiguous by virtue of theedge of the structural member. In one embodiment as illustrated in FIG.10A, the grooves 1020 are oriented such that a component of blood flowalong the leading edge 1014 exposes EC within the grooves 1020 to shearstress caused by the blood flow. Similarly, the trailing edge 1016 ofthe structural member 1006, in one embodiment, may have topographicalfeatures such as grooves 1022 disposed therein or thereon. The grooves1022 may be oriented in any direction relative to the direction 1010 ofblood flow. In one embodiment as illustrated in FIG. 10A, the grooves1022 are oriented such that a component of blood flow along the trailingedge 1016 exposes EC within the grooves 1022 to shear stress caused bythe blood flow.

It should be noted that the topographical features on one or more of thesurfaces 1036, 1014, 1016, may take any of a variety of forms, and arenot limited to the grooves discussed above. For example, any or all ofthe grooves 1018, 1020, 1022 illustrated in FIG. 10A may alternativelybe dots, divots, pores, holes, complex geometries, and/or the like.

Any of the geometrically functional features or recesses may also beincluded in the trailing edge, leading edge, or surface regions toenhance the endothelial migration and attachment to such surfaces.

An implantable device may include problematic surfaces that may beresistant to endothelialization or may otherwise be relatively slow toendothelialize. The problematic surfaces may be disadvantaged for celladhesion because of, for example, hemodynamic reasons such as disruptionvia turbulence or low shear stress (which may occur in thick stents, forexample, greater than about 100 μm) or chemical reasons such asanti-mitotic and/or anti-inflammatory drugs. The problematic surfacescould be, for example, stent bridges disposed at various angles againstthe blood flow.

Referring to FIG. 10b , it is contemplated that a combination ofproperly oriented grooves may facilitate EC migration to the problematicsurfaces and/or promote cell stability thereon. For example, in oneembodiment, a main highway 1000 of the grooves 1018 may be disposed inthe luminal surface 1036 of the structural member 1006 and orientedgenerally parallel to the direction 1010 of blood flow, as illustratedin FIG. 10b . The main highway 1000 could provide an abundance ofmigrating EC, which could be diverted therefrom to a problematicsurface, for example, a surface 1002 on a transversely disposedstructural member 1007 of the implantable device. For example, the mainhighway 1000 may be diverted to groove endpoints 1054 on thetransversely disposed structural member 1007 of the implantable device.

It is further contemplated that diversion of migrating EC from the mainhighway 1000 could be applied to surfaces having a specific function,and is noncontiguous by virtue of the diversion, which may or may nototherwise be conducive to EC migration. In some embodiments, themachined pattern may include features which pin or demote cellproliferation, so as to stop cell proliferation in a particularlocation. These patterns may be used to steer cells to control adirectionality of healing response. In some embodiments, and withoutlimitation, these features may be pores, holes, divots, and/or the like.FIG. 10b illustrates one embodiment of a surface with directional andpinning topographical features created thereupon. For example, referringto FIG. 10B, the structural member 1007 may include surfaces including aplurality of pores 1008 as might be found, for example, in a drugeluting stent. The plurality of pores may act to pin cell proliferationin the location of the pores 1008, and demote proliferation beyond thelocation of pores 1008.

In another embodiment of the present invention, the machined pattern mayinclude features which pin or demote cell proliferation. These patternsmay be used to steer cells to control a directionality of healingresponse. FIG. 10b illustrates one embodiment of a surface withdirectional topographical features created thereupon.

In one embodiment, a first pattern may be applied to a first surface ofa dental implant, and a second pattern may be applied to a secondsurface of the dental implant. The first surface may serve to promoteadhesion and healing of the implant in the bony part of the jaw, whilethe second surface may serve to stop proliferation of bone into the gumline.

Additional applications where it may be advantageous to demote healinginclude, without limitation, temporary implants such as a vena cavafilter or an insulin pump needle.

In any embodiment of the present invention, an existing medical device,stent, or other article may be utilized. Through the use of an existingstructure, it is likely that the regulatory path may be minimized.

Particular, non-limiting examples of medical devices that may be workedupon by the inventive method disclosed herein include dental implants,hip implants, and valves. Other devices may also be worked upon, aspreviously discussed above.

FIG. 11a depicts one embodiment of a textured dental implant 1100 havingtopographical features created thereupon. The dental implant 1100 has aportion imparted with a noncontiguous texture 1120 to promote bonegrowth in the jaw bone and a portion imparted with a dotted texture 1140to pin the cells so they don't proliferate into the gums. In thedepicted embodiment, the noncontiguous texture is alternating triangulargrooved features that run along the length of the implant 1100, toprovide directional migration of cells and thereby promote bone growthalong and into the portion of the implant 1100 that is installed intothe jaw bone of a patient. The portion of the implant 1100 having adotted texture 1140 serves to halt the proliferation of cell growth suchthat the bone growth does not continue into the gums of the patient. Theideal texture for the bone growth may be a crosshatch to add ananchoring effect to the dental implant 1100. FIG. 11b is an enlargedview of the noncontiguous portion 1120 having displaced hexagonalgrooved features and dotted portion 1140 of the dental implant 1100. Inalternative embodiments, the features of the grooved portion 1120 mayhave different arrangements and/or noncontiguous shapes, such asnoncontiguous grooves that run diagonally, noncontiguous grooves thatrun helically, complex geometries that promote bone growth along thelength of the implant, features having multiple depths, and/or the like.The portion of the implant 1100 having a dotted texture 1140 maycomprise divots, pores, holes, wells, and/or the like, serving to pincells in place and thereby demote cell proliferation beyond the dottedportion 1140. In alternative embodiments, the features of the dottedportion 1140 may have different arrangements and/or shapes, or theportion may have greater or lesser width or height.

FIG. 12a depicts one embodiment of a textured hip implant 1200 havingtopographical features created thereupon. The hip implant 1200 has aportion imparted with a noncontiguous grooved texture 1220 to promotebone growth and a portion imparted with a dotted texture 1240 to pin thecells so they don't proliferate beyond the dotted portion. In thedepicted embodiment, the grooves are an alternating hexagonal patternthat run along the length of the implant 1200, to providemulti-directional migration of cells and thereby promote bone growthalong and into the portion of the implant 1200 that is installed intothe bone of a patient. The portion of the implant 1200 having a dottedtexture 1240 serves to halt the proliferation of cell growth such thatthe bone growth does not continue into the joint of the patient. Theideal texture for the bone growth may be a crosshatch to add ananchoring effect to the hip implant 1200. FIG. 12b is an enlarged viewof the grooved portion 1220 that includes an noncontiguous triangularfeatures and dotted portion 1240 of the hip implant 1200. In alternativeembodiments, the features of the noncontiguous grooved portion 1220 mayhave different arrangements and/or shapes, such as noncontiguous groovesthat run diagonally, noncontiguous grooves that run spirally, complexgeometries of features that promote bone growth along the length of theimplant, features having multiple depths, and/or the like. The portionof the implant 1200 having a dotted texture 1240 may comprise divots,pores, holes, wells, and/or the like, serving to pin cells in place andthereby demote cell proliferation beyond the dotted portion 1240. Inalternative embodiments, the features of the dotted portion 1240 mayhave different arrangements and/or shapes, or the portion may havegreater or lesser width or height. FIG. 12C shows the noncontiguousgrooved portion 1220 on the distal portion including a first directionof the triangular grooves and a second direction of the triangulargrooves 1220 a in direction generally at an angle to the first directionof the grooves on the side of the implant.

FIG. 13a depicts one embodiment of a textured heart valve 1300 havingtopographical features created thereupon. The heart valve 1300 has aportion imparted with a grooved texture 1320 to promote cell growthwhere the heart valve 1300 is anchored to the tissue, and a portionimparted with a dotted texture or noncontiguous elliptical pattern 1340to pin the cells so they don't proliferate into the valve portion of theheart valve 1300. In the depicted embodiment, the grooves run along thelength of the struts on the heart valve 1300, to provide directionalmigration of cells and thereby promote cell growth along and into theportion of the implant 1300 that is anchored into the heart of apatient. The portion of the heart valve 1300 having a noncontiguouselliptical pattern 1340 serves to halt the proliferation of cell growthsuch that the cell growth does not continue into the valve portion. Theideal texture for the cell growth may be a crosshatch to add ananchoring effect to the heart valve 1300. FIG. 13b is an enlarged viewof the grooved portion 1320 and dotted portion 1340 of the heart valve1300. In alternative embodiments, the features of the grooved portion1320 may have different arrangements and/or shapes, such as grooves thatrun diagonally, grooves that run helically, complex geometries thatpromote cell growth along the length of the implant, features havingmultiple depths, and/or the like. The portion of the heart valve 1300having a dotted texture 1340 may comprise divots, pores, holes, wells,and/or the like, serving to pin cells in place and thereby demote cellproliferation beyond the dotted portion 1340. In alternativeembodiments, the features of the dotted portion 1340 may have differentarrangements and/or shapes, or the portion may have greater or lesserwidth or height.

In still further alternative embodiments of the present invention, thedevices modified could be more “industrial” in nature, rather than beingmedical devices. One such example is an earring post or stem (or otherpiercing articles), which may have its surface modified with anoncontiguous pattern of topographical features to prevent hole closure,infection, etc.

All documents and references cited herein are incorporated by referencein their entireties.

It is to be understood that the invention is not limited to the exactdetails of construction, operation, exact materials, or embodimentsshown and described, as obvious modifications and equivalents will beapparent to one skilled in the art. Accordingly, the invention istherefore to be limited only by the scope of the appended claims.

What is claimed:
 1. An implantable medical device having at least onefluid or tissue contacting surface, a depth defined by sidewalls of theimplantable medical device, and a longitudinal axis, comprising: aplurality of elongate grooves in the fluid or tissue contacting surface,at least some of the plurality of elongate grooves further having grooveendpoints that are oriented orthogonally relative to a longitudinal axisof an elongate groove having a groove endpoint; and a plurality of poresin the fluid or tissue contacting surface, at least some of theplurality of pores being in proximity to the groove endpoints.
 2. Theimplantable medical device according to claim 1, wherein some of theplurality of elongate grooves are positioned in the sidewalls of theimplantable medical device and extend parallel to plurality of elongategrooves in the fluid or tissue contacting surface of the implantablemedical device.
 3. The implantable medical device according to claim 2,further comprising a plurality of pores in the sidewalls of theimplantable medical device.
 4. The implantable medical device accordingto claim 3, wherein the plurality of pores in the sidewalls of theimplantable medical device are positioned in proximity to the elongategrooves in the sidewalls of the implantable medical device.
 5. Theimplantable medical device of claim 1, further comprising anintravascular stent or stent-graft.
 6. The implantable medical device ofclaim 5, wherein the plurality of grooves are disposed along a majorityof the fluid or tissue contacting surface of the implantable medicaldevice.
 7. The implantable medical device of claim 1, wherein at leastsome of the plurality of elongate grooves have a length of at least0.1-5.0 microns.
 8. The implantable medical device according to claim 2,wherein some of the elongate grooves are positioned in the sidewalls ofthe implantable medical device and extend orthogonally to the pluralityof elongate grooves in the sidewalls of the implantable medical device.